Session Type: Abstract Submissions (ACR)
Background/Purpose: Both IL-6 and IL-21 have been described to drive in vitro Th17 differentiation in the presence of TGF-β. We explored whether also in vivo IL-6 and IL-21 play an exchangeable and redundant role in Th17 differentiation during experimental arthritis, and to what extent combined blocking of these cytokines inhibits Th17 differentiation and suppresses arthritis development.
Methods: To investigate possible synergistic effects of the IL-6 and IL-21 pathways, arthritis development and Th17 cells were first studied in IL-6-/-xIL-21R-/- mice and their wild-type (WT) and single-knockout controls during antigen-induced arthritis (AIA). In addition, the effects of combined IL-6R and IL-21 neutralization were studied in DBA-1J mice treated at various stages of collagen-induced arthritis (CIA).
Results: Mice deficient for either IL-6 or IL-21R showed suppressed AIA compared to WT controls. This disease reduction was accompanied by a significant reduction in CD4+IL17+ T cells in the draining lymph nodes as determined by FACS. Interestingly, mice lacking both the IL-6 and IL-21 signaling pathways showed even stronger disease suppression, and a striking reduction in Th17 levels was observed in these mice.
Based upon these findings, we aimed to confirm the synergistic effects of IL-6/IL-21 with a cytokine-neutralization approach using anti-IL-6R antibodies and sIL-21R-Fc treatment during CIA. Antibodies were given as single treatment or in combination, starting from immunization (day 0) or simultaneous with the booster (day 21).
Combined blocking of IL-6R and IL-21 early during arthritis development (day 0) was a very potent approach to prevent arthritis development, reaching a disease incidence of only 40% at day 35 (isotype control 100%, sIL-21R-Fc 100%, anti-IL-6R 60%). Analyzing the mice that did develop arthritis, we observed that the anti-IL-6R/sIL-21R-Fc combination was also clearly more potent in suppressing the arthritis severity in comparison with the single treatments. Interestingly, blocking the IL-6/IL-21 pathways at a later stage during arthritis development (day 21) was clearly less effective and did not show additional effects to anti-IL-6R treatment alone.
Conclusion: Combined blocking of the IL-6 and IL-21 pathways suppresses Th17 differentiation in vivo as demonstrated by our IL-6/IL-21R-deficient mice. However, our neutralization study during CIA shows that to influence arthritis development this IL-6/IL-21 blocking approach only has a limited therapeutic window. These findings suggests that to target Th17-driven joint pathology, blocking Th17 effector cytokines like IL-17 and IL-22 might be more effective than attempting to reduce Th17 cell numbers during active disease.
D. M. Roeleveld,
M. I. Koenders,
R. J. Marijnissen,
C. L. Nickerson-Nutter,
F. A. van de Loo,
W. B. van den Berg,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/combination-blocking-of-interleukin-6-and-interleukin-21-in-experimental-arthritis-inhibits-their-redundant-role-in-t-helper-17-driven-joint-pathology/